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Mardis Interview14
Mardis Interview14
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enzymes and things would happen and you could evaluate and
actually see them. Drosophila geneticists would probably laugh and
say that I was too stupid to get my head around the questions they
address, and this might be true, but to me molecular biology just
seemed so much more interesting.
Weve known since the 1970s when Janet Rowley and others
starting looking under the microscope at chromosomes that there is
clearly something genomically different about cancer cells. In a way,
we now have a very finely tuned microscope that looks at DNA at
the single-nucleotide resolution, but ultimately tells us the exact
same thing. People lose sight of the fact that the major purpose
behind the Human Genome Project was to understand the cause of
human disease. Once we had a finished blueprint, this was the
natural direction to move in.
My first foray into cancer came in 2003-2004, in partnership with
Harold Varmus and his young trainee William Pao, both then at
Memorial Sloan Kettering. At that point in time, a small proportion
of lung cancer patients were being given new drugs called tyrosine
kinase inhibitors, and about 10% of these patients were experiencing
a tremendous benefit. That a drug could clear lung lesions in
metastatic patients within a few short weeks was just miraculous.
However, there was the question of the other 90% who werent
responding. We took a handful of patients from Harold and
Williams studies of tyrosine kinases and lung cancer and said:
Right, we have a limited ability to look at the genome lets find
out whats different about tyrosine kinase genes in these patients
who are responding versus those who dont. We knew that there are
key tyrosine kinases that act as drivers in cancer, and we inferred
that these are probably the ones being targeted by tyrosine kinase
inhibitor drugs. Sequencing revealed that patients who showed a
dramatic response to these drugs had a key series of mutations
throughout the tyrosine kinase region of epidermal growth factor
receptor. We reported this coincident with two other groups, and so
all the papers got published together. It was really our first
experience of doing something great and tangible with the human
reference genome we had helped to sequence.
Another contributor to my training in cancer care was afforded by
the role I played as Basic and Translational Sciences Director for the
American College of Surgeons Oncology Group, one of the NCI
[National Cancer Institute]-funded cooperative groups. This
exposure to the organization, conductance and analysis of clinical
trials was incredibly important in helping me to understand basic
concepts of oncology, clinical care and standard practice. I also
learned how drugs are approved for use in patients, and about the
basics of clinical trial design. I was further rewarded in this
experience by being able to include samples from ACOSOG clinical
trials in some of the genomics studies we have done at my institute.
I recall that when I started working within ACOSOG, I felt like I
knew nothing about cancer, clinical trials, clinical care paradigms
and how genomics would fit into this arena. Nowadays, Im
feeling much more comfortable in the cancer genomics space,
mainly because Ive had the chance to be involved with a lot of the
key people who are leading this area. Its one of the real advantages
Cancer is the easiest and most obvious one, with the caveat that it is
neither easy nor obvious at times. For cancer diagnoses, our group
plans to apply what I call the Maserati approach a three-pronged
approach in which the whole genome of tumor and normal is
combined with information at the exome (tumor and normal) and
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human health. If you cant get along and respect what other people
bring to the table, youre not going to be deemed a good collaborator
and you are not going to be invited to participate. It sounds obvious,
but I think sometimes science, particularly biology, can have some
singularity to it. In the past, you could end up with an illustrious
career working independently, but I think were now in a very
different era. To have maximum impact, we have to be in a
collaborative setting and we have to be collaborative.
How do you relax outside of the lab?
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